Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005391.5(PDK3):c.608C>G(p.Thr203Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T203T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 22)

Consequence

PDK3
NM_005391.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.61

Publications

0 publications found

Variant links:

Genes affected

PDK3 (HGNC:8811): (pyruvate dehydrogenase kinase 3) The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2). It provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle, and thus is one of the major enzymes responsible for the regulation of glucose metabolism. The enzymatic activity of PDH is regulated by a phosphorylation/dephosphorylation cycle, and phosphorylation results in inactivation of PDH. The protein encoded by this gene is one of the three pyruvate dehydrogenase kinases that inhibits the PDH complex by phosphorylation of the E1 alpha subunit. This gene is predominantly expressed in the heart and skeletal muscles. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

PDK3 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease X-linked dominant 6
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

PDK3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005391.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDK3	NM_005391.5	MANE Select	c.608C>G	p.Thr203Arg	missense	Exon 6 of 11	NP_005382.1
	PDK3	NM_001142386.3		c.608C>G	p.Thr203Arg	missense	Exon 6 of 12	NP_001135858.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PDK3	ENST00000379162.9	TSL:1 MANE Select	c.608C>G	p.Thr203Arg	missense	Exon 6 of 11	ENSP00000368460.4
PDK3	ENST00000568479.2	TSL:6	c.608C>G	p.Thr203Arg	missense	Exon 6 of 12	ENSP00000498864.1
PDK3	ENST00000648777.1		n.608C>G		non_coding_transcript_exon	Exon 6 of 12	ENSP00000497727.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease X-linked dominant 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.60

MetaRNN

Uncertain

0.67

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.93

PhyloP100

5.6

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.96

REVEL

Uncertain

0.37

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.022

Polyphen

0.29

Vest4

0.80

MutPred

0.45

Loss of ubiquitination at K205 (P = 0.0924)

MVP

1.0

MPC

1.1

ClinPred

0.76

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

Mutation Taster

=25/75

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs1555949588

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over